Unable to reach the end zone through three quarters, the Saints got a pair of touchdown passes from Brees to Marques Colston in the final 15 minutes to beat the Titans 22-17 on Sunday.
"It was a gut-check win for us," New Orleans coach Sean Payton said. "A lot of things early on didn't go our way. We had some calls that could have went either way. We just kept fighting and won a good game on the road against a good team."
Now the Saints (10-3) have won five straight and remain in the lead of the NFC South with three games left in the regular season. They clinched a playoff berth when the Chicago Bears lost in overtime to the Denver Broncos later Sunday.
They got another strong performance from Brees, who joined Hall of Famer Johnny Unitas as the only quarterbacks to throw a touchdown pass in 40 straight games.
On third-and-6, Brees threw 35 yards to a wide-open Colston, who jumped into the air just in front of the goal line at the middle of the field, caught the ball and fell forward into the end zone, making it 16-10 with 12:39 to play.
The Saints converted two third downs on their next drive before Brees connected again with Colston on a scoring pass, this time for 28 yards.
The touchdown gave New Orleans a 22-10 lead with 7:01 left, and Colston finished with 105 yards on seven catches.
"We knew they were going to get yards," Tennessee safety Michael Griffin said. "Drew knows how to dissect a defense."
Brees was 36 for 47 for 337 yards and completed passes to nine different Saints. He has 39,413 yards passing in 150 career starts, which ranks just behind the 39,498 yards passing Dan Marino achieved in his first 150 starts.
The Titans (7-6) twice had the ball in the final minutes with a chance to win.
Their loss allowed the Houston Texans, which won at Cincinnati on Sunday, to clinch the AFC South and kept them from gaining any ground in a crowded race for the second AFC wild-card spot.
"As bad as this one's going to hurt ... we can't let this one cost us anymore games," Titans coach Mike Munchak said. "We have three games, we have to win all three games."
Faced with another fourth down at the Saints 24 with 2:18 left, Locker kept the ball. Though a replay seemed to show he picked up the needed yard, the officials ruled him down with no gain, and the Titans did not challenge the ruling.
Tennessee held New Orleans on the next drive, and Washington caught a 40-yard pass from Locker with 27 seconds left, setting up another chance for a Titans rally.
Locker spiked the ball at the Saints 5 to stop the clock, but his pass on second down to Marc Mariani in the end zone was batted down by Tracy Porter, and Jo-Lonn Dunbar sacked a scrambling Locker on third down as time expired.
"I was just hoping they didn't throw a flag. I kind of grabbed him by the helmet," Dunbar said. "It was definitely a lot of relief to see those guys jumping, and with that excitement, you can't put a price tag on that."
The rookie quarterback entered the game with the score 3-3 with 11:13 left in the second quarter, replacing Matt Hasselbeck.
Hasselbeck hurt his left calf after trying to chase a pass of his that had been tipped and left the field and watched most of the game from the sideline, filling in for Locker on a single play after the backup took a hard hit.
Locker was 13 for 29 for 282 yards and a touchdown, and Washington finished with 130 yards on six catches and a score. Johnson, who was coming off consecutive games with more than 150 yards rushing, had just 23 yards on 11 carries.
Locker ran for a second touchdown, scrambling around the right end and meeting Roman Harper at the corner of the end zone. He stretched the ball over the pylon with his right hand as he spun in the air, and the play was upheld on review to make it 10-9 with 2:19 in the third quarter.
Washington caught a 40-yard TD pass from Locker and broke a tackle before tripping into the end zone to cut New Orleans' lead to 22-17 with 5:58 left.
Penalties and other mistakes kept New Orleans' league-leading offense from getting any rhythm through three quarters, and three times the Saints got within 11 yards of the end zone only to settle for a field goal. John Kasay kicked field goals of 29, 25 and 22 yards to help the Saints build a 9-3 third-quarter lead.
The Saints also missed another scoring opportunity early in the first half. Darren Sproles returned a punt 82 yards to the end zone, but the score was negated on a holding call on Dunbar.
The only other time the Saints didn't score a touchdown in the first half was in their 31-21 loss at St. Louis on Oct. 30.
Payton and Brees together are 20-0 in games where the Saints don't turn the ball over. ... New Orleans improved to 4-3 in road games. ... Klug entered the game leading Tennessee in sacks, and his two against New Orleans gives him six for the season. ... Brees extended his NFL-record streak of games with 20 or more completions to 33. ... The Saints' victory ended a streak of four wins by the Titans in the 13-game series between the teams.
Matt Hasselbeck will start at quarterback for the Indianapolis Colts on Thursday night when they visit the Houston Texans, according to a league source.
Dallas Cowboys coach Jason Garrett spoke with defensive end Greg Hardy regarding his comments about returning "guns blazing," and about the wife of New England Patriots quarterback Tom Brady.
Cowboys owner Jerry Jones was a little taken aback Wednesday when informed of linebacker Greg Hardy's curious choice of words to describe his return.
Roddy White, who was away from the team Wednesday as his mother underwent surgery, rejoined his teammates Thursday and had a cordial conversation with Falcons coach Dan Quinn about his role.
The Patriots have signed running back Dion Lewis, a surprise contributor for them this season, to a two-year contract extension through the 2017 season, a league source said.
Former NFL Coach of the Year Lindy Infante, who was 36-60 with the Packers and Colts in six seasons as a head coach, died in Florida at age 75.